Медицинская библиотека · medRxiv : the preprint server for health sciences · 2024

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.

Dharmadhikari Avinash V, Abad Maria Alba, Khan Sheraz, Maroofian Reza, Sands Tristan T, Ullah Farid, Samejima Itaru, Wear Martin A, Moore Kiara E, Kondakova Elena, Mitina Natalia, Schaub Theres, Lee Grace K, Umandap Christine H, Berger Sara M, Iglesias Alejandro D, Popp Bernt, Jamra Rami Abou, Gabriel Heinz, Rentas Stefan, Rippert Alyssa L, Izumi Kosuke, Conlin Laura K, Koboldt Daniel C, Mosher Theresa Mihalic, Hickey Scott E, Albert Dara V F, Norwood Haley, Lewanda Amy Feldman, Dai Hongzheng, Liu Pengfei, Mitani Tadahiro, Marafi Dana, Pehlivan Davut, Posey Jennifer E, Lippa Natalie, Vena Natalie, Heinzen Erin L, Goldstein David B, Mignot Cyril, de Sainte Agathe Jean-Madeleine, Al-Sannaa Nouriya Abbas, Zamani Mina, Sadeghian Saeid, Azizimalamiri Reza, Seifia Tahere, Zaki Maha S, Abdel-Salam Ghada M H, Abdel-Hamid Mohamed, Alabdi Lama, Alkuraya Fowzan Sami, Dawoud Heba, Lofty Aya, Bauer Peter, Zifarelli Giovanni, Afzal Erum, Zafar Faisal, Efthymiou Stephanie, Gossett Daniel, Towne Meghan C, Yeneabat Raey, Wontakal Sandeep N, Aggarwal Vimla S, Rosenfeld Jill A, Tarabykin Victor, Ohta Shinya, Lupski James R, Houlden Henry, Earnshaw William C, Davis Erica E, Jeyaprakash A Arockia, Liao Jun

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Аннотация

SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, we identified 24 individuals with neurodevelopmental delays from 18 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants showed reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicated that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 revealed that most disease-associated missense variants mapped to the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants had reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS ( SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

Для цитирования: Dharmadhikari Avinash V, Abad Maria Alba, Khan Sheraz, Maroofian Reza, Sands Tristan T, Ullah Farid, Samejima Itaru, Wear Martin A, Moore Kiara E, Kondakova Elena, Mitina Natalia, Schaub Theres, Lee Grace K, Umandap Christine H, Berger Sara M, Iglesias Alejandro D, Popp Bernt, Jamra Rami Abou, Gabriel Heinz, Rentas Stefan, Rippert Alyssa L, Izumi Kosuke, Conlin Laura K, Koboldt Daniel C, Mosher Theresa Mihalic, Hickey Scott E, Albert Dara V F, Norwood Haley, Lewanda Amy Feldman, Dai Hongzheng, Liu Pengfei, Mitani Tadahiro, Marafi Dana, Pehlivan Davut, Posey Jennifer E, Lippa Natalie, Vena Natalie, Heinzen Erin L, Goldstein David B, Mignot Cyril, de Sainte Agathe Jean-Madeleine, Al-Sannaa Nouriya Abbas, Zamani Mina, Sadeghian Saeid, Azizimalamiri Reza, Seifia Tahere, Zaki Maha S, Abdel-Salam Ghada M H, Abdel-Hamid Mohamed, Alabdi Lama, Alkuraya Fowzan Sami, Dawoud Heba, Lofty Aya, Bauer Peter, Zifarelli Giovanni, Afzal Erum, Zafar Faisal, Efthymiou Stephanie, Gossett Daniel, Towne Meghan C, Yeneabat Raey, Wontakal Sandeep N, Aggarwal Vimla S, Rosenfeld Jill A, Tarabykin Victor, Ohta Shinya, Lupski James R, Houlden Henry, Earnshaw William C, Davis Erica E, Jeyaprakash A Arockia, Liao Jun. RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.. medRxiv : the preprint server for health sciences. 2024. DOI: 10.1101/2024.01.09.23300329.

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